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Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice
Haiyun Ling, … , Donald Bers, Joan Heller Brown
Haiyun Ling, … , Donald Bers, Joan Heller Brown
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1230-1240. https://doi.org/10.1172/JCI38022.
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Research Article

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Abstract

Ca2+/calmodulin–dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIδ, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIδ deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIδ contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIδ activation can limit the progression to heart failure.

Authors

Haiyun Ling, Tong Zhang, Laetitia Pereira, Christopher Kable Means, Hongqiang Cheng, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Ju Chen, Donald Bers, Joan Heller Brown

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Enhanced PI3K-Akt signaling, but not CaMKIIγ, compensates for loss of CaMKIIδ in mediating hypertrophic responses

Submitter: Wenjun Yan | fgao@fmmu.edu.cn

Authors: Wenjuan Xing, Haifeng Zhang, and Feng Gao.

Department of Physiology and Department of Cardiology, Xijing Hospital, Fourth Military Medical University

Published May 17, 2009

To the Editor: In the article by Ling et al, hypertrophy induced by pressure overload was comparable in CaMKIIδ KO and WT mice 2 weeks after transverse aortic constriction (TAC). They explained that CaMKIIγ probably compensates for the loss of CaMKIIδ in mediating hypertrophic responses [1].

Although CaMKIIγ was similarly upregulated and activated after TAC [1,2], accumulating evidence did not support that CaMKIIγ compensates for the loss of CaMKIIδ and contributes to the hypertrophic response to pressure overload. First, CaMKIIγ subunit is only expressed at low level in cardiomyocytes while the CaMKIIδ is predominant isoform in the heart [2,3]. Second, if CaMKIIγ could compensate for the loss of CaMKIIδ, the expression of CaMKIIγ should be significantly higher at 2 weeks after TAC in CaMKIIδ KO mice compared with WT mice. However, CaMKIIγ level was about the same in the two groups as shown in Figure 3A in their paper [1]. Third, the two isoforms, i.e., CaMKIIγ and CaMKIIδ, are different in subcellular localization, intracellular targeting, Ca2+ and/or Ca2+/CaM sensitivity, suggesting their distinct properties and specificity in the signal transduction pathway [3].

Hypertrophy occurs after physiological or pathological stimulation without significant difference in morphology. Multiple physiological hypertrophy signaling pathways are triggered by pressure load, including phosphoinositide 3-kinase (PI3K)-Akt [4]. The PI3K-Akt signaling pathway dominates in the regulation of physiological developmental hypertrophy and may act as an upstream modulator of protein kinase Cβ2 (PKCβ2), with potential for rescuing the pathological cardiac dysfunction [5]. TAC increased Akt activity as shown both by the ratio of phosphorylated to total Akt protein expression and by activity assay [4]. Therefore, it is probable that TAC-induced hypertrophy in CaMKIIδ KO mice is associated with the increased PI3K-Akt signaling, rather than the CaMKIIγ signaling pathway. This explanation is consistent with studies showing that CaMKIIδ inhibition or deletion preventing maladaptive remodeling and heart failure [1,6], because β-AR/CaMKII signaling was decreased after CaMKIIδ inhibition or deletion while PI3K-Akt signaling was comparably enhanced.

References

  1. Ling, H.Y., et al. 2009. J. Clin. Invest. 119(5): 1230-1240.
  2. Colomer, J.M., et al. 2003. Mol Endocrinol. 17(2):183-192.
  3. Zhang, T., et al. 2004. Cardiovasc Res. 63(3):476-486.
  4. Takimoto, E., et al. 2005. Nat. Med. 11(2):214-222.
  5. Rigor, D.L., et al. 2009. Am J Physiol Heart Circ Physiol. 296(3): 566-572.
  6. Zhang, R., et al. 2005. Nat. Med. 11(4):409-417.

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